The Hsp90-associated enzyme-FK506 binding protein 51 (FKBP51)-was recently found to co-localize with tau in neurons and physically interact with the microtubule (MT)-associated protein tau in brain tissue from humans who died from Alzheimer's disease (AD). More recently, protein levels of FKBP51 were shown to increase in forebrain neurons with age, further supporting a novel role for FKBP51 in tau processing. The goal of this study is to determine how FKBP51 regulates the biology of tau and whether it is a rational therapeutic target for treating AD, Parkinson's disease (PD), and other tauopathies. Tau aggregation is a central component of Alzheimer's disease (AD) and ~15 other neurodegenerative diseases termed tauopathies. It is now clear that the individual components of the chaperone system exist in an intricate signaling network that can exert pleiotropic effects on tau, facilitating either its degradation or stabilization. Therefore, we endeavored to identify new ways to specifically regulate individual components of the chaperone family that may be targets for therapeutic development. The Hsp90 cochaperone, FKBP51, which possesses both an Hsp90 interacting tetratricopeptide (TPR) domain and a cis-trans peptidyl-prolyl cis-trans isomerase (PPIase) domain, was found to prevent tau clearance and regulate its phosphorylation status. Regulation of the latter is dependent on the PPIase activity of FKBP51. Hsp90 enhances the association of tau with FKBP51, and clearance of tau facilitated by FKBP51 knockdown is dependent on Hsp90 variants. In vitro, FKBP51 stabilizes microtubules with tau in a reaction dependent on FKBP51 PPIase activity. Based on these new findings we propose the following aims to determine the role of FKBP51 in tau biology and pathogenesis. We will 1) investigate how FKBP51 regulates the structural ensembles and aggregation kinetics of tau, 2) determine whether FKBP51 utilizes discreet Hsp90 variants to regulate distinct tau species, and 3) determine whether genetic manipulation of FKBP51 in the brain alters tau-based pathologies and phenotypes in a transgenic mouse model of tauopathy. PUBLIC HEALTH RELEVANCE: The tau protein accumulates in more than 15 neurodegenerative diseases collectively termed tauopathies, the most common being Alzheimer's disease. Despite this fact, only one drug is currently in clinical trials that targets the tau protein. This is largely due to our lack of understanding of how the brain deals with tau under normal circumstances. Here, we have identified a novel protein that interacts with tau and may represent a novel therapeutic target to treat Alzheimer's disease. This protein, FKBP51, can promote tau removal through a very interesting mechanism, and we will explore whether manipulation of this protein can clear tau protein from the brain. These studies may lead to drug development that can provide sufferers of tauopathies a way to combat their condition, with the ultimate goal being a cure.